Persistent Symptoms After Acute COVID-19 Infection in Omicron Era

Since late 2019, coronavirus disease 2019 (COVID-19) infection has continued to spread worldwide, rendering an ongoing pandemic. Until May of 2022, more than 500 million have been infected worldwide, and more than 18 million have been infected in South Korea. Compared to previous variants, the omicron variant has evaded and transmitted the human immune system, thereby infecting many populations within South Korea.1, 2, 3

It is known that these persistent symptoms could remain as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through the COVID-19 pandemic over the past two years.4, 5, 6, 7 Previous studies on long-term sequelae after illness by other coronavirus type infections—SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV)—have been reported in the literature.8, 9 However, the consensus on the definition and criteria for these sequelae has not been established. The World Health Organization (WHO) defines “Long COVID” as the case in which symptoms persist for greater than two months; the Centers for Disease Control and Prevention (CDC) defines it as symptoms even after four weeks following acute disease, whilst the European Society of Clinical Microbiology and Infectious Disease (ESCMID) indicates symptoms even after 12 weeks post-infection.4, 10, 11 The ESCMID established a working definition for the purpose of categorization as follows: 1) symptoms persisting for 12 weeks after COVID-19 diagnosis were defined as “Long COVID”, whereas 2) those persisting between 4 to 12 weeks were defined as “Post-acute COVID”.2

The persistent symptoms after COVID-19 infection have also been reported in the literature.12, 13, 14 The clinical manifestation differs according to corresponding variants, and therefore the sequelae are also expected to be different.1 There are few reports on “Post COVID-19 Conditions” of the omicron variant. The prevalence of the omicron variant in South Korea dates back to its onset in November of 2021. Thereafter it was considered the most dominant species in February of 2022, prolonging and contributing to the unprecedented magnitude of the current pandemic. Myongji Hospital first opened the “Post COVID-19 Clinic” in South Korea. The center treated 1,122 patients presenting with post COVID-19 conditions from March 21 through April 22. Based on the data from our “Post COVID-19 Clinic”, we aim to compare the clinical characteristics and presenting symptoms of the acute COVID phase (< 4 weeks since the onset of COVID-19 infection) and that of the post-acute COVID phase (> 4 weeks since the onset of COVID-19 condition) in order to examine which factors may have plausible effects on the number of persistent symptoms and their respective categories.

In this study, we examined whether the number and categories of persistent symptoms were different according to their duration following an acute infection among 1,122 patients who responded to a questionnaire pertaining to persistent symptoms after COVID-19 infection, HADS and FSS. We observed that the number of symptoms and their categories were higher in the post-acute group than in the acute group. The prevalence of some symptoms such as fatigue, decreased attention, depression, blurred vision, hair loss, and sexual dysfunction were higher in the post-acute group than in the acute group. HADS-Anxiety, HADS-Depression, FSS and age were associated with the number of symptoms and their categories and anxiety was the most correlated factor. Our findings suggest that the persistent symptoms of post COVID-19 condition involved multi-organ systems with a duration of four weeks or greater which required long-term observation and multidisciplinary intervention.

Our results are not different from previous studies on the long-term effects of COVID-19 infection before the emergence of the omicron variant. In 2020, the CDC COVID-19 response team reported 270 infected patients after two to three weeks from the time of diagnosis.19 Herein, 175 patients (65%) fully recovered to baseline health status and the median value of the recovery period was 7 days; however, 95 patients (35%) had subjective complaints of persistent symptoms. Persistent symptoms were reported as follows: cough (43%), fatigue (35%), and dyspnea (29%).19 Goërtz et al.12 followed 2,113 patients for three months during which time 85.3% of women reported symptoms of fatigue, shortness of breath, and headache. A study by Jennings et al.,13 assessed patients during the acute period after infection, similar to our study, and reported fatigue (43%), shortness of breath (31%), cough (26%), insomnia (36%), and anosmia (11%) as persistent symptoms. The most common symptoms reported in another study were fatigue, shortness of breath, and myalgia.14 Similar to previous studies, the high incidence in women is likely to be associated with a higher incidence of autoimmune diseases among women.12, 14

In this study, the rate of pneumonia diagnosis rate was 2.8%, which was lower than in previous studies.13, 14 This is likely attributable to the fact that the omicron variant primarily causes upper respiratory tract infection, and the disease severity has decreased compared to previous variants due to the widespread implementation of COVID-19 vaccinations and spike protein mutation. Furthermore, the majority of our observed results in this study are thought to be due to the participation of home-based treatment patients with no hospitalization history.

The mechanism of persistent symptoms long after COVID-19 infection is currently not well understood. It is presumably caused by tissue damage from the SARS-CoV-2 virus binding action to human angiotensin-converting enzyme 2 which is expressed in multiple organs including lungs, brain, heart, gastrointestinal tract, liver, pancreas, kidneys, and blood vessels. Viral infection can bind to various organs and cause direct damage which can lead to persistent symptoms.20, 21 An immune response like an autoimmune response caused by a viral infection can also cause persistent symptoms. Although the role and immune mechanism of T cells in SARS-CoV-2 infection are not fully known, it is known that immune system dysregulation may occur, such as an autoimmune response.22, 23 Moreover, there are hypotheses on the underlying culprits for persistent symptoms including pathophysiologic manifestations such as hidden viral reservoirs and non-infectious viral fragments, COVID-19 associated immune exhaustion, abnormal immunometabolism, mitochondrial dysfunction, altered microbiome, and imbalance in the renin-angiotensin system.24

The symptom patterns were different across the two groups. In acute group, respiratory symptoms associated with viral infections were dominant, and this may be associated with an inflammatory response caused by residual levels of the virus or their fragments. As the virus level subsides respiratory symptoms improve. Other symptoms are thought to be potentially related to immune response without any significant difference as it relates to time. In the post-acute group, common symptoms were fatigue, psychiatric symptoms such as anxiety, depression, and decreased attention. Persistent symptoms after infection are affected by some psychological factors contributing to rates of infection as was the case with persistent symptoms after SARS-CoV and MERS-CoV infection.8, 9 However, although anxiety belonged to Category B, depression and fatigue fell under Category C. Therefore, unlike anxiety, the prevalence of depression and fatigue appears to have increased as persistent symptoms continued. In the post-acute group, the prevalence of blurred vision, hair loss, and urologic and gynecologic symptoms were higher than that of the acute group. The pathogenesis of these symptoms with low prevalence involving multiple systems is unclear and thus future studies on the underlying mechanism are warranted.

WHO International Classification of Disease-10 system has approved “Post COVID-19 Condition (U-09)” for post-acute sequelae of COVID-19 since September of 2020. However, the definition of the “Post COVID-19 Condition” has not been substantiated. The sequelae are also on a continuum from the onset of the disease thereby adding to the challenge of clearly elucidating the course of ongoing disease. Based on our experience from the designated clinic for “Post COVID-19 Condition,” the demand for medical treatment arises immediately following the completion of an isolation period. It is necessary to delineate and characterize the long-term effects of COVID-19 infection that is different from the ongoing symptoms of COVID-19.

This is the first study on “Post COVID-19 Conditions” after the omicron variant breakthrough infection in South Korea, and we believe that it provides new insight into its underlying clinical manifestations during the transition period from acute infection to long COVID syndrome. Our study also presented some limitations. A prospective longitudinal cohort study design may serve to be more advantageous than the retrospective cross-sectional design. Subjective complaints of symptoms were acquired using a questionnaire with limited objective test results to support our hypothesis. Since there is a lack of consensus in defining post COVID-19 condition, all patients who presented to the clinic with varying subjective symptoms were included for data acquisition whereas patients with severe omicron variant infections were selectively excluded. Future studies are warranted to substantiate criteria and analysis of associated symptoms in depth by stratification of severity or underlying comorbidity. Although several studies have reported associations between COVID-19 vaccinations and post COVID-19 conditions, our data did not include the vaccination status.25, 26

In conclusion, there are varying symptoms which persist following a COVID-19 infection. As reported in our study, we observed many subjective complaints of post COVID symptoms after an omicron variant infection. In the protracted acute phase of COVID-19 infection (< 4 weeks from the infection of COVID-19), it is essential for medical management to primarily target respiratory-related symptoms whereas a multidisciplinary systems approach to clinical care is advantageous during the post-acute phase (> 4 weeks from the infection of COVID-19).